At an average age between 45 and 52 years, in the women there is a gradual decline of the ovarian function ending with the cessation of ovulation and of the endocrine secretion of sexual hormones. This condition is called menopause and is connected with a number of unpleasant symptoms, such as hot flushes, sweats, insomnia, vaginal dryness and depression. In the long term the estrogen deficiency leads to a generalized atrophy of the skin, loss of hairs, urogenital atrophy and dysfunction, accelerated bone loss from the skeleton producing osteoporosis and rapid increase of the incidence of coronary heart diseases. All these adverse sequelae can be reversed by an appropriate replacement therapy with estrogen agents, i.e. by the "Hormone Replacement Therapy.sub.-- (HRT).
Several types of estrogens are used for the HRT, e.g. conjugated equine estrogens, estradiol, estrone, etc., with a preference for estradiol which is the most potent physiological estrogen hormone.
Estradiol can be administered by parenteral or oral route. The oral administration has several problems, because estradiol is almost insoluble in water and its bioavailability is scarce and largely depending on the galenical formulation and physical properties of the active substance. Therefore the bioavailability is very variable even in the same subject. In addition, estradiol undergoes to a intense first pass effect in the intestine and in the liver, with the formation of several metabolites. These metabolites greatly loss the estrogen potency but maintain some adverse effects, including the increase of risk of cancer. In addition the oral administration provokes very large and unphysiological fluctuations of the hormonal blood levels and exposes the subjects to an unnecessary load of estrogen substances.
The ideal administration route, because closest to the physiological secretion of estradiol, would be the intravenous slow infusion. This administration is evidently not practicable. Similar pharmacokinetic pattern as with intravenous slow infusion can be obtained by transdermal administration, because by this route the liver is bypassed and estradiol is directly supplied to the circulation. Furthermore the transdermal release of estradiol is rather constant, similar to that occurring physiologically from the ovary, without the daily large fluctuations which characterize the oral administration.
The most convenient dosage form for the transdermal administration is the "Transdermal Patch.sub.--, i.e., according to the European Pharmacopoea, "flexible pharmaceutical preparations of various sizes, containing one or more active ingredients. They are intended to be applied on the unbroken skin in order to deliver the active ingredient(s) to the systemic circulation after passing through the skin barrier.sub.--.
Different types of transdermal patches were developed. The first used for estradiol is a liquid reservoir patch (U.S. Pat. No. 4,379,454) which contains estradiol in an alcoholic gel solution. The diffusion of estradiol to the skin is controlled by a rate limiting membrane. This type of patch needs the presence of a solubilizer of estradiol which has also the function of absorption enhancer and is represented by ethanol. From this type of patches estradiol is released rapidly in the first 1-2 days, and then more slowly. Therefore the estradiol concentrations in blood during a 3-4 day application of this patch are not constant. Furthermore the presence of alcohol produces skin irritation in a certain number of patients. For these reasons the liquid reservoir type patches are more and more replaced by the solid matrix patches of the new generation, in which estradiol is incorporated into the adhesive matrix which adheres directly to the skin.
In women with intact uterus the estradiol replacement therapy often produces hypertrophy of the endometrium which may lead to endometrial cancer. To prevent this risk the estrogen therapy in women with intact uterus must be intermittently "opposed by the administration of a progestogen agents, to provoke a menstruation-like cleavage and renewal of the endometrial mucosa. In general the progestogen opposition is obtained administering by oral route for 10-14 days a progestogen, such as progesterone, medroxyprogesterone acetate, dydrogesterorie, norethisterone, etc.
Obviously a transdermal patch containing estradiol and progestogen would be more practical than the transdermal estrogen administration combined with the oral progestogen administration. The inclusion of the progestogen in an transdermal patch, however, faces several obstacles, first of all the relatively high doses of the progestogen needed to have an efficient opposition. In most cases these high doses cannot be vehicled in a transdermal patch. Further obstacles are the instability and the scarce solubility of most progestogens.